PROJECT SUMMARY ? Project 6 Ovarian cancer remains the deadliest gynecological cancer, underscoring the need for better treatment options. Our published work demonstrates that PKC?, a PKC isoform not targeted by PKC inhibitors previously tested in the clinic, is an oncogene in ovarian and non-small cell lung cancer (NSCLC), where it plays critical roles in tumor initiation and progression. PKC? is also genetically activated in the most common serous ovarian tumor subtype: ~80% of high grade serous ovarian tumors exhibit PRKCI copy number gains associated with elevated PKC? expression. Interestingly, our published and preliminary data demonstrate that PKC? drives tumorigenesis in the ovary by a distinct, novel mechanism not observed in other tumors. Specifically, our preliminary studies indicate that: 1) ovarian cancer cells are ?addicted? to PKC? such that genetic or pharmacologic inhibition of PKC? leads to loss of ovarian cell growth and viability; 2) PKC? maintains a chemoresistant phenotype in ovarian cancer cells characterized by stem-like behavior, enhanced resistance to cisplatin and enhanced tumorigenicity; 3) PKC? activates a novel oncogenic PKC?- SOX2-HIPPO/YAP1 signaling pathway in these chemoresistant tumor-initiating cells (TICs); and 4) a novel small molecule PKC? inhibitor developed in collaboration with a pharmaceutical partner inhibits proliferation and viability of both bulk tumor cells and chemoresistant TICs. Based on these data we hypothesize that: 1) PKC? maintains a chemoresistant phenotype, in part, through activation of HIPPO/YAP1 signaling; 2) a novel PKC? inhibitor will effectively inhibit this pathway and block ovarian cancer cell transformed growth; 3) high grade serous ovarian cancers harboring PRKCI amplification and PKC? overexpression are ?addicted? to PKC? and will, therefore, be more responsive to PKC? inhibition than tumors without this genetic characteristic; 4) components of oncogenic PKC?-SOX2- HIPPO/YAP1 signaling can be developed as pharmacodynamic biomarkers of PKC? inhibition and possible predictive biomarkers of ovarian cancer sensitivity to PKC? inhibitor therapy; 5) a highly potent and specific PKC? inhibitor will effectively inhibit tumor PKC? and exhibit anti-tumor activity in a first-in-human therapeutic trial. These hypotheses will be tested through completion of three interrelated specific aims to: 1) dissect the mechanism by which PKC? regulates chemoresistant ovarian cancer cell behavior and assess the effect of PKC? inhibition on these cells; 2) assess the effect of PKC? inhibitor on primary serous ovarian cancer growth and validate biomarkers of response to PKC? inhibition using well validated patient-derived xenograft models; and 3) assess the ability of a highly potent and specific PKC? inhibitor to inhibit PKC? clinically in a first-in-human phase I clinical trial. Collectively, these studies will provide the first rigorous test of the hypothesis that PKC? can be targeted for therapeutic benefit in ovarian cancer.